One of the several intriguing mysteries of multiple sclerosis (MS) is the variability of the clinical course. Some people have rather severe forms of MS, leading to marked disability and dysfunction, while others may have a course so mild that it is not diagnosable or even noticeable, except as a surprise finding at autopsy. This variability has led some to conclude that MS might be a syndrome or spectrum of different disorders rather than a single disease.
This variability has long been recognised, but a standardisation of the terms used to describe the clinical courses of MS was not undertaken until 1995. At that time a committee of the National Multiple Sclerosis Society (USA) undertook the task of codifying the clinical courses in an attempt to unify the course descriptions. The need for this had become more acute as MS had just entered the disease treatment era and new clinical trial designs needed to utilise more similar groups of subjects. Further, there was speculation at that time, which has since been supported by more recent clinical trial results, that response to disease-modifying agents might be different for the various sub-types of MS.
At that time, we looked to see if there were reliable ways to measure the disease course – called markers. The advent of readily available magnetic resonance imaging (MRI) has greatly aided the diagnosis of MS. This led to new diagnostic guidelines, called the McDonald’s criteria, in which MRI features play an important role in the diagnostic process, allowing for easier and earlier reliable diagnosis of the illness. After discussions with imaging experts, we concluded that there were no MRI features that distinguished the clinical sub-types of MS.
Similarly, a search for a laboratory biomarker in blood or cerebrospinal fluid was unsuccessful. The absence of a validated, reproducible biomarker for the disease course still eludes us, although very interesting and promising immunologic and genetic markers are under active investigation. We were left with trying to develop a consensus on the course definitions.
This was accomplished through a survey of members of the international MS clinical research community. Of the 215 persons sent the survey, 125 responded and their responses were the basis for the course definitions employed. In addition to the course definitions, definitions of benign and malignant MS were developed.
The course definitions developed are as follows:
Relapsing-remitting (RRMS) is characterised by clearly defined disease relapses* with full recovery or with some after affects upon recovery. Periods between disease relapses are characterised by a lack of disease progression. The defining elements of RRMS are episodes of acute worsening of neurologic function followed by a variable degree of recovery, with a stable course between attacks. The period of time between relapses is highly variable.
Primary progressive (PPMS) is defined as disease progression from onset with occasional plateaus and temporary minor improvements. The essential element in PPMS is a gradual, nearly continuously worsening with minor fluctuations, but no distinct relapses.
Secondary progressive (SPMS) is characterised by an initial relapsing-remitting disease course followed by progression with or without occasional relapses, minor remissions and plateaus.
SPMS may be seen as a long-term outcome of RRMS, in that most people with SPMS initially had RR disease as defined here. However, once the baseline between relapses begins to progressively worsen, the person is considered to have switched from RRMS to SPMS.
Progressive-relapsing (PRMS) is defined as progressive disease from onset, with clear acute relapses, with or without recovery, with periods between relapses characterised by continuing progression. Although the least common of the subtypes, recent clinical trials of progressive MS have provided ample evidence for this form of MS. The behaviour of PRMS is similar to that of SPMS.
A relapse – also called an exacerbation, attack or flare – is a period when people with MS experience new symptoms or when their old symptoms reoccur, followed by complete or partial recovery. To be a true relapse, it must last at least 24 hours and be separated from the previous one by at least 30 days. Most relapses last from a few days to several weeks or even months.
One could think about grouping these disease courses into relapsing forms and progressive forms of MS. The relapsing forms would encompass RR, SP and PR MS. This characterisation has been utilised in some clinical trials and also has been used in regulatory labelling of drugs by the US Food and Drug Administration (the regulatory body which approves drugs in the US). Progressive forms of MS would encompass PP, PR and SP MS. This has also been utilised in clinical trials. Although there are overlaps between these two combined groups, they offer certain advantages in clinical trial design, so long as it is clear which types of MS are being studied.
Since the publication of these MS subtypes, two additional disease courses have been described. The inelegantly named ‘clinically isolated syndrome’ (CIS) refers to the first episode of inflammatory demyelination that occurs in those who are eventually to be diagnosed as RRMS. Current diagnostic rules require the identification of two relapses separated in time and involving different areas of the central nervous system – so individuals with CIS are not diagnosable with MS. Yet clinical trials of such individuals demonstrate that, when properly chosen, this group has a high probability of conversion to MS. Less clear is what is now being referred to as the ‘radiologic isolated syndrome’ (RIS, also referred to recently as CIS type 5). This designation is applied to individuals who have MRI scans for reasons unrelated to MS and are found to have changes on these scans suggestive of (asymptomatic) MS. Recent reports have expanded our understanding of this group, but much more information is needed.
As mentioned above, the clinical course definitions will benefit from the development of discriminative MRI and biomarker data. Once available, we should be better able to employ these disease course definitions for making prognoses and deciding on the best treatment for each individual.
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